Unlike other tissues which can survive extended periods of hypaxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockage of synaptic transmission or by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman et al, Annals of Neurology, 19, No. 2 (1986)]. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS). Glutamate is believed to be a mixed agonist capable of binding to and exciting all three receptor types.
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
It is known that compounds of various structures, such aminophosphonovalerate derivatives and piperidine dicarboxylate derivatives, may act as competitive antagonists at the NMDA receptor. In particular, compounds such as 2-amino-4-(2-phosphonomethylphenyl)butyric acid and 2-(2-amino-2-carboxy)ethylphenylphosphonic acid have been synthesized for evaluation as antagonists in blocking the action of the neurotransmitter compounds L-glutamic acid and L-aspartic acid [K. Matoba et al, Chem. Pharm. Bull., 32 (10), 3918-3925 (1984)].
There is other evidence that the NMDA receptor complex is involved in multiple physiological and pathological events, inasmuch as the NMDA receptor complex is a ligandgated ion channel that can be modulated by diverse substances acting at distinct recognition sites. For example, there is evidence that polyamines including spermine and spermidine profoundly enhance the binding of channel ligands, such as [.sup.3 H]TCP(N-1-[2-thienyl]cyclohexyl)piperidine) and [.sup.3 H]dizocilipine (MK-801) by acting as agonist modulators, like glycine. Polyamines may act by increasing the frequency of channel opening or by increasing the duration of the open state.
Certain piperidineethanol derivatives, such as ifenprodil and 1-(4chlorophenyl)-2-[1-(4-fluorophenyl)piperidinyl]ethanol, which are known anti-ischemic agents, have been found to be noncompetitive NMDA receptor antagonists [C. Carter et al, J. Pharm Exp. Ther., 247 (3), 1222-1232 (1988)]. Also, tritiated and iodinated ifenprodil molecules have been employed to examine the characteristics of the polyamine domain of the NMDA receptor-complex [P. M. Beart et al, Neurosci. Lett., 124, 187-189 (1991)].
It has been found that ifenprodil has considerable affinity for the sigma site in vitro [P. C. Contreras et al, Neurosci. Lett., 116, 190-193 (1990)]. Sigma binding affinity has also been found in vivo and it has been further suggested that sigma ligands may have neuroprotective properties [J. Benavides et al, Neurosci. Abstracts, 16, 541 (1990)].
There are many classes of compounds known for treatment of psychotic disorders. For example, current therapeutic treatments for psychoses use compounds classifiable as phenohiazine-thioxanthenes, as phenylbutylpiperidines and also as certain alkaloids. An example of a phenylbutylpiperidine compound of current use in psychotic treatment therapy is haloperidol [A. F. Gilman et al, The Pharmcological Basis of Therapeutics, 7th Edn., p. 404, MacMillan (1985)].
The reference `Collection Czechoslov. Chem. Comun.`, 39 (2), 617-623, 1974, describes some phenylaminoethanols which in certain cases and mostly high doses posess a CNS-activity. These are 1-(5-indanyl)-2-amino-N,N-n-butyl-methylethanol, 1-(5-indanyl)-2-amino-N-phenylmethylpiperazinoethanol and 1-(5-indanyl)-2-amino-N-cycloheptyl-ethanol.
The reference Arch. Int. Pharm., 266 (2), 264-281, 1983 discloses the antihypertensive effect of Tibalosine--a t ienylphenyl-aminoethanol--which is said to also exhibit anxiolytic activity. The reference, however, is silent with respect to a NMDA-antagonisic and neuro-protective effect of said compound.